Alzheimer's disease (AD) is an age-related, neurodegenerative disease that is one of the leading causes of dementia afflicting 1% of people under the age of 60 to more than 40% of people over the age of 85. The symptoms of this disease are typified by memory loss and a progressive decline of cognitive abilities. This disease is characterized by the extracellular deposition of amyloid-beta (Ab) aggregates known as plaques that are surrounded by dystrophic neurites and activated glial cells as well as intracellular neurofibrillary tangles that are comprised of hyperphosphorylated tau protein aggregates. As detailed in the February 2006 Alzheimer's Research Forum, one of the most critical needs in AD research is the identification of biomarkers that can not only predict disease but also monitor responses to treatment. In this project, we first propose to utilize a novel MRI methodology, Manganese Enhanced MRI (MEMRI) that we helped develop to delineate the role of AB on in vivo axonal transport rates and pre-synaptic release and post-synaptic uptake mechanisms in mouse models of AD. Second, we will test MEMRI as an in vivo neuroimaging diagnostic to assess and potentially detect very early on responses to treatment in mouse models of AD. Third, we will determine if Ab1- 40, Ab1-42 or the combination of the two species contributes to in vivo changes in axonal transport and pre- synaptic release and post-synaptic uptake mechanisms in mouse models of AD.